• BMB Reports
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• v.49 no.11
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• pp.617-622
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• 2016

Oxidative stress is closely associated with various diseases and is considered to be a major factor in ischemia. NAD(P)H: quinone oxidoreductase 1 (NQO1) protein is a known antioxidant protein that plays a protective role in various cells against oxidative stress. We therefore investigated the effects of cell permeable Tat-NQO1 protein on hippocampal HT-22 cells, and in an animal ischemia model. The Tat-NQO1 protein transduced into HT-22 cells, and significantly inhibited against hydrogen peroxide ($H_2O_2$)-induced cell death and cellular toxicities. Tat-NQO1 protein inhibited the Akt and mitogen activated protein kinases (MAPK) activation as well as caspase-3 expression levels, in $H_2O_2$ exposed HT-22 cells. Moreover, Tat-NQO1 protein transduced into the CA1 region of the hippocampus of the animal brain and drastically protected against ischemic injury. Our results indicate that Tat-NQO1 protein exerts protection against neuronal cell death induced by oxidative stress, suggesting that Tat-NQO1 protein may potentially provide a therapeutic agent for neuronal diseases.

• Journal of Physiology & Pathology in Korean Medicine
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• v.22 no.4
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• pp.835-840
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• 2008

Acupuncture has long been contended to be effective in an ischemic stroke. A real-time monitoring of glutamate, an excitotoxin in the process of ischemic neuronal damage, in the striatum is tried in a rat model of global ischemia. Global ischemia was induced by the 11 vessel occlusion method for 10 minutes, during which acupuncture stimulation on GB34 and GB39 points was executed. Glutamate release in the rat striatum was monitored 256 times per second using real-time amperometric biosensor. Real time measurement data of 10 minutes prior to the induction of ischemia served as baseline data. Data acquisition continued for 30 minutes after the initiation of reperfusion. Peak concentration of glutamate release along with incidentally measured EEG and cerebral blood flow was compared between cases with and without acupuncture stimulation. Peak concentration of glutamate lowered when acupuncture stimulation was executed. A real time monitoring system of 11 vessel-occlusion induced global ischemia model was successfully established. The effect by acupuncture on acute global ischemia was successfully observed in this real-time monitoring setting, which may be one of the neuroprotective mechanism of acupuncture.

• The Journal of Internal Korean Medicine
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• v.31 no.4
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• pp.763-774
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• 2010

Objectives : In condition of brain infarction, irreversible axon damage occurs in central nerve system(CNS), because gliosis becomes physical and mechanical barrier to axonal regeneration. Reactive gliosis induced by ischemic injury such as middle cerebral artery occlusion is involved with up-regulation of GFAP and CD81. The current study is to examine the effect of the Uncariae Ramulus et Uncus on CD81 and GFAP expression in the rat brain following middle cerebral artery occlusion. Methods : In order to study ischemic injuries on brain, infarction was induced by middle cerebral artery occlusion(MCAO) using insertion of a single nylon thread, through the internal carotid artery, into a middle cerebral artery. Cresyl violet staining, cerebral infarction size measurement, immunohistochemistry and microscopic examination were used to detect the expression of CD81 and GFAP and the effect on the infarct size and pyramidal cell death in the brain of the rat with cerebral infarction induced by MCAO. Results : The following results were obtained 1. Measuring the size of cerebral infartion induced by MCAO in the rat after injection of Uncariae Ramulus et Uncus showed the size was decreased. 2. Intravenous injection of Uncariae Ramulus et Uncus showed pyramidal cell death protection in the hippocampus in the MCAO rat. 3. Water extract injection of Uncariae Ramulus et Uncus decreased GFAP expression significantly in the MCAO rat. 4. Uncariae Ramulus et Uncus water extract decreased CD81 expression in the MCAO rat. 5. The administration of water extract of Uncariae Ramulus et Uncus induced up-regulation of c-Fos expression significantly compared with MCAO. 6. The admistration of water extract of Uncariae Ramulus et Uncus increased ERK expression significantly compared with MCAO. Conclusion : We observed that Uncariae Ramulus et Uncus could suppress the reactive gliosis, which disturbs the axonal regeneration in the brain of the rat with cerebral infaction after MCAO by controlling the expression of CD81 and GFAP. The effect may be modulated by the up-regulation of c-Fos and ERK. These results suggest that Uncariae Ramulus et Uncus can be a candidate to regenerate CNS injury.

• Clinical and Experimental Pediatrics
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• v.52 no.1
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• pp.105-110
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• 2009

Purpose : Perinatal asphyxia is an important cause of neonatal mortality and subsequent lifelong neurodevelopmental handicaps. Although many treatment strategies have been tested, there is currently no clinically effective treatment to prevent or reduce the harmful effects of hypoxia and ischemia in humans. Erythropoietin (Epo) has been shown to exert neuroprotective effects in various brain injury models although the exact mechanisms through which Epo functions are not completely understood. This study investigates the effect of Epo on hypoxic-ischemic (HI) brain injury and the possibility that its neuroprotective actions may be associated with iron-mediated metabolism. Methods : HI brain injury was produced in 7-day-old rats by unilateral carotid artery ligation followed by hypoxia with 8% oxygen for 2 h. At the end of HI brain injury, the rats received an intraperitoneal injection of 5,000 units/kg erythropoietin. Random premedication with iron, deferoxamine, iron-deferoxamine, or saline were performed 23 d before HI brain injury. The severity of the brain injury was assessed at 7 d after HI. Results : Single Epo treatment post-HI brain injury reduced the gross and histopathological findings of brain injury. Iron premedication did not increase the incidence or severity of the injury as measured by the damage score. Deferoxamine administration before HI brain injury improved the brain injury as compared to no treatment or Epo treatment. Conclusion : These findings indicate that Epo provides neuroprotective benefits after HI in the developing brain. These findings suggest that Epos neuroprotective actions may involve reducing iron in tissues that mediate the formation of free radicals.

• BMB Reports
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• v.49 no.7
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• pp.382-387
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• 2016

Reactive oxygen species generated under oxidative stress are involved in neuronal diseases, including ischemia. Glutathione S-transferase pi (GSTpi) is a member of the GST family and is known to play important roles in cell survival. We investigated the effect of GSTpi against oxidative stress-induced hippocampal HT-22 cell death, and its effects in an animal model of ischemic injury, using a cell-permeable PEP-1-GSTpi protein. PEP-1-GSTpi was transduced into HT-22 cells and significantly protected against H2O2-treated cell death by reducing the intracellular toxicity and regulating the signal pathways, including MAPK, Akt, Bax, and Bcl-2. PEP-1-GSTpi transduced into the hippocampus in animal brains, and markedly protected against neuronal cell death in an ischemic injury animal model. These results indicate that PEP-1-GSTpi acts as a regulator or an antioxidant to protect against oxidative stress-induced cell death. Our study suggests that PEP-1-GSTpi may have potential as a therapeutic agent for the treatment of ischemia and a variety of oxidative stress-related neuronal diseases.

• Biomolecules & Therapeutics
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• v.9 no.3
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• pp.167-175
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• 2001

Recent studies have shown that cytokines are capable of modulating cardiovascular function and that some drugs used in the treatment of heart failure variably modulate the production of cytokines. Hige- namine, a positive inotropic isoquinoline alkaloid, has been used traditionally as cardiac stimulant, and reported to reduce nitric oxide (NO) and inducible nitric oxide synthase (iNOS) expression in LPS- and/or cytokine-activated cells in vitro and in vivo. Therefore, we investigated whether higenamine modulates the production of proinflammatory cytokines in myocardial infarction. In addition, effects of higenamine on antioxidant action and antioxidant enzyme expression (MnSOD) were studied. Myocardial infarction (MI) was confirmed by measuring left ventricular (LV) pressure after occlusion of the left anterior descending coronary artery (LAD) for 5 weeks in rats. Treatment of higenamine (10 mg/kg/day) reduced infarct size about 35 %, which accompanied by reduction of production TNF-$\alpha$, IL-6, but not IFN-${\gamma}$ and IL-1$\beta$ in the myocardium. The expression of TNF-$\alpha$ mRNA in infracted myocardium was significantly reduced by higenamine. Although iNOS mRNA was not detected, nitrotyrosine staining was significantly increased in myocardium of Ml compared to higenamine-treated one, Indicating that peroxynitrite-induced damage is evident in MI. Cytochrome c oxidation by peroxynitrite was concentration-dependently reduced by higenamine, an effect which was almost compatible to glutathion. Higenamine treatment did not affect the expression of MnSOD mRNA in myocardial tissues in MI. Taken together, higenamine may be beneficial in oxidative stress conditions such as ischemic-reperfusion injury and MI due to antioxidant action as well as modulation of cytokines.

• Journal of Chest Surgery
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• v.25 no.1
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• pp.1-16
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• 1992

The quantitatively measured local myocardial perfusion rates with microspheres are used as an objective indicator of even distribution of cardioplegic solution, and the efficacy of the retrograde right atrial route of cardioplegia is evaluated in hearts with various levels of coronary arterial obstruction. After initial antegrade cardioplegia under the median sternotomy and aortic cannulation, 60 hearts from anesthetized New Zealand white rabbits are divided in random order as normal group [ligated left main coronary artery ; MA, MR] and diagonal group [ligated proximal diagonal artery ; LA, LR]. Half of each group [N=10] are perfused with antegrade cardioplegia[A] under the pressure of 100 cmH2O and the other half with retrograde right atrial route[R] under the pressure of 60 cmH2O[St. Thomas cardioplegic solution mixed with measured amount of microspheres]. The myocardium is subdivided into segments as A[atria], RV[right ventricle]. S[septum], LV[normally perfused left ventricular free wall], ROI[ischemic myocardium of left ventricular free wall]. LV and RQI are further divided into N[subendocardium] and P[subepicardium]. The resulting local myocardial perfusion rates and N /P of each group are compared with Wilcoxon rank sum test. The weight of the hearts is 5.94$\pm$0.66g, and there are no statistically significant dif-ferences[p>0.05, ANOVA] between six compared group. The mean flow rate[F: ml /g / min] of MR group is comparable with MA group[p>0.05], but in N and L group, there are significantly depressed F with right atrial route of cardioplegia, which means elevated perfusion resistance with this route. In spite of no significant differences in delivered doses of microsphere[DEL] between compared groups[p>0.05, ANOVA], there are significantly depressed REC and NF in hearts with right atrial cardioplegia which suggests increased requirement of cardioplegic solution with this route. The interventricular septum shows poor perfusion with right atrial route of cardioplegia without obstruction of supplying coronary arteries. But, with obstruction of coronary artery supplying septum as in M group, the flow rate is superior with right atrial route of infusion. The left ventricular free wall perfusion rates of every RQI with R route are superior to that of A route[p<0.05]. But, in LV segments, there are unfavorable effects of right atrial cardioplegia in L group, although the subendocardial perfusion is well maintained in N group. The LV free wall of left main group shows depressed perfusion rates with antegrade route as compared with RQI segments of diagonal group. But, by contraries, there are increased perfusion rates and superior N /P ratio with retrograde right atrial route. It implies more effective perfusion with right atrial route of cardioplegia in more proximal coronary arterial obstruction[i.e., M group as compared with L group]. As a conclusion, all region of ischemia have superior perfusion rates with right atrial car-dioplegia as compared with antegrade route, and especially excellent results can be obtained in hearts with more proximal obstruction of coronary arteries which would otherwise result in more severe ischemic damage. But, the depressed perfusion rates of the segments with normal coronary artery in hearts with coronary arterial obstruction may be a problem of concern with right atrial cardioplegia and needs solution.

• Journal of Life Science
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• v.30 no.7
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• pp.651-659
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• 2020

Cardiovascular disease is one of the leading causes of death across the world, and gold-standard treatments such as percutaneous coronary intervention and artery bypass grafting have various limitations including myocardial damage and subsequent maladaptive cardiac remodeling. To overcome this, stem-cell therapies are emerging as a promising strategy for cardiovascular regeneration. Endothelial progenitor cells (EPCs) have high potential to proliferate and differentiate into endothelial cells for vascularization and tissue regeneration, and several clinical trials have explored EPC function in tissue repair in relation to clinical safety and improving cardiac function. Consequently, EPC has been suggested as a feasible stem-cell therapy. However, autologous EPC transplantation in cardiovascular disease patients is restricted by risk factors such as age, smoking status, and hypertension that lead to reduced bioactivity in the EPCs. New approaches for improving EPC function and stem-cell efficacy have therefore been suggested, including cell priming, organoid culture systems, and enhancing transplantation efficiency through 3D bioprinting methods. In this review, we provide a comprehensive understanding of EPC characteristics, therapeutic approaches, and the current state of clinical research into EPCs as stem-cell therapy for cardiovascular disease.

• Korean Journal of Clinical Laboratory Science
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• v.51 no.3
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• pp.370-378
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• 2019

The hepatic ischemic model has recently been widely used for the epidemiological study of ischemic reperfusion injury. This study was carried out to investigate the protective effect of vanillin, which is known to have antioxidant and anti-inflammatory effects, against hepatic and renal injury using an ischemia-reperfusion rat model, and we also investigated the mechanism related to vanillins' protective effect. The test material was administered at a concentration of 100 mg/kg for 3 days, followed by ligation of the liver for 60 minutes to induce ischemia reperfusion. As control groups, there was a negative control, sham control and ischemia-reperfusion-only ischemia reperfusion control, and the controls groups were compared with the drug administration group. In the vanillin group, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were significantly inhibited compared with the AST and ALT activities of the ischemia-reperfusion group, and histopathological examination showed significant reduction of both inflammation and necrosis. The malondialdehyde (MDA) and superoxide dismutase (SOD) levels were significantly different from the ischemia-reperfusion group. In conclusion, vanillin showed a hepatocyte protective action by alleviating the cellular inflammation and cell necrosis caused by hepatic ischemia-reperfusion, and vanillin mitigated inflammatory changes in the kidney glomeruli and distal tubules. The protective effect is considered to be caused by vanillin's antioxidant function. Further studies such as on cell death and possibly vanillin's same effect on damaged tissue will be necessary for clinical applications such as organ transplantation.

• The Journal of Internal Korean Medicine
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• v.23 no.2
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• pp.181-190
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• 2002

The water extract of Omija-tang(OMJT) has been traditionally used for treatment of ischemic heart and brain damage in oriental medicine. However, little is known about the mechanism by which the water extract of OMJT protects cells from such damage. Therefore, this study was conducted to investigate the protective mechanisms of OMJT on $H_2O_2$-induced toxicity in H9c2 cardiomyoblast cells. Treatment of $H_2O_2$ markedly induced death of H9c2 cardiomyoblast cells in a dose-dependent manner. The characteristics of $H_2O_2$-induced death of H9c2 showed apparent apoptotic features, such as DNA fragmentation. However, OMJT significantly reduced both $H_2O_2$-induced cell death and chromatin fragmentation. The decrease of Bcl-XL expression by $H_2O_2$ was inhibited by OMJT. In addition, the increase of Bcl-XS and Bax expression were also inhibited by OMJT. In particular, Fas expression, which is generally recognized as cell death inducing signal by Fas/FasL interaction, was markedly increased by $H_2O_2$ in a time-dependent manner, whereas this increase was completely prevented by OMJT. The combined treatment of OMJT and $H_2O_2$ in H9c2 cells also reduced activation of caspase-9 and caspase-3 like protease. Taken together, this study indicates that the protective effects of the water extract of OMJT against oxidative damage may be mediated by the modulation of BcI-XL/S and Bax expression by way of the regulation of mitochondrial membrane potential and caspase cascades.